Psychopharmacology Research Tutorial for Practitioners - Antidepressant Drugs: Is a Dual Mechanism Better?

Donald S. Robinson, MD

Primary Psychiatry. 2004;11(8):17-18

The Monoamine Hypothesis of Depression

In the 1950s the serendipitous and nearly
simultaneous discovery of the first antidepressant medications,
iproniazid and imipramine, predated any understanding of the
pharmacologic mechanism of action of drugs effective for the treatment
of depressive disorders. Iproniazid was subsequently found to inhibit
monoamine oxidase, the enzyme that degrades monoamine
neurotransmitters, while imipramine was discovered to inhibit reuptake
of monoamines released at nerve terminals. To a large extent,
discovery of the pharmacologic actions of these antidepressants
fostered promulgation of the catecholamine and monoamine hypotheses of
depression. Enhancement of monoamine neurotransmitter function
remains the putative mechanism of action of all antidepressants even
today. Whether norepinephrine (NE) or serotonin (5-hydroxytryptamine
[5-HT]) is the more critical neurotransmitter in the pathophysiology
and treatment of depression is still an open question.

5-HT was an early candidate for acting as mediator of
mood in the central nervous system (CNS) because of its presence in
key brain regions, its structural similarity to lysergic acid
diethylamide, and the fact that reserpine, an antihypertensive agent
that can cause depression, depletes neuronal stores of monoamines,
especially intracellular serotonin.1 The focus later
shifted from 5-HT to NE as the more critical neurotransmitter in
depressive disorders. This was based primarily on the seminal work of
Nobel laureate Julius Axelrod, who found NE to be widely distributed
in the CNS and synaptically released at adrenergic nerve endings, with
its reuptake into the neuron inhibited by tricyclic antidepressants
(TCAs). Arvid Carlsson, also a Nobel laureate, subsequently found that
clomipramine, a TCA widely used in Europe for treating depression,
inhibited 5-HT reuptake to a greater extent than NE reuptake.1

It became apparent during extensive investigation
that individual TCAs varied considerably in their ability to affect
either or both 5-HT and NE transporter systems. Imipramine and
amitriptyline, two of the most widely prescribed TCAs, were found to
inhibit reuptake of 5-HT and NE to a similar extent. The monoamine
oxidase inhibitors (MAOIs), which in the 1960s gained initial clinical
popularity as being broadly effective antidepressants,2 had
long been known to increase neuronal stores of both 5-HT and NE in the
brain by inhibiting the catabolism of monoamines.

Gradually, a large body of data accumulated showing
that both MAOIs and TCAs essentially functioned as dual-mechanism
antidepressants. Even though the pharmacologic mechanisms of action of
these antidepressants were understood, how exactly this translated
into producing antidepressant treatment response remains unclear.
Depending on the specific drug, differing monoamine neurotransmitter
systems might be involved, and cause an antidepressant response.
Another unanswered dilemma revolves around why the onset of clinical
benefit for all antidepressants is typically delayed for up to several
weeks, while the pharmacologic effects of antidepressants are evident
nearly immediately.

Selectivity of Reuptake Inhibition

It was not until the 1970s that the first selective
inhibitor of monoamine reuptake was synthesized. Zimelidine, the first
selective serotonin reuptake inhibitor (SSRI), was marketed only in
Europe and was followed soon thereafter by fluoxetine, the first SSRI
in the United States. These two drugs were the forerunners of a new
and highly successful class of antidepressants. SSRIs proved to be
broadly effective in the treatment of mood disorders, but more
importantly, they were also better tolerated and safer than TCAs and
MAOIs because of their highly specific affinity for the 5-HT
transporter system. This pharmacology translated into a desirable
therapeutic profile (of lower toxicity than earlier antidepressants)
and led to the wide popularity of these drugs among general physicians
as well as psychiatrists.

The clinical effectiveness of the selectively-acting
5-HT drugs for mood disorders resulted in a rethinking of the roles
that 5-HT and NE played in the pathophysiology of depressive disorders
and in the treatment of depression. Within the pharmaceutical
industry, the search for new antidepressants shifted to highly
specific receptor affinity and targeting either the 5-HT or NE system
in order to discover drugs with fewer side effects and/or enhanced
efficacy.

Several relatively specific norepinephrine reuptake
inhibitors (NRIs) have proven to be clinically effective
antidepressants and are still available, including the TCAs
desipramine, nortriptyline, and protriptyline, as well as the
tetracyclic drug maprotiline. The NRI reboxetine was approved recently
for antidepressant use in Europe but is not available in the US. Since
NRIs have been shown to be effective antidepressants, this leads to
the question of whether NE might be the primary neurotransmitter in
depressive disorders and a preferred target for new antidepressant
development. Recent data show that increased brain NE levels may
prevent neuronal atrophy in the cortex by enhancing nerve growth
factors and possibly augmenting the beneficial effects of NRIs.3

Single Versus Dual Mechanisms of Uptake Inhibition

Although the advent of the SSRIs unquestionably
altered antidepressant prescribing patterns—with the additional effect
that significantly more depressed patients now receive drug treatment
than a decade ago—SSRIs have also acquired a reputation, perhaps
undeserved, as being less effective than the older antidepressants
that involve dual mechanisms of action. Two recent drugs, venlafaxine
and duloxetine, which act by inhibiting both the 5-HT and the NE
transporters with high specificity, have been touted as “dual
mechanism antidepressants,” with the inference that they potentially
have superior efficacy compared with single mechanism antidepressants.4
The claim of superior therapeutic benefits of these dual mechanism
drugs remains controversial because of a paucity of data from
well-controlled comparative studies (ie, prospective trials
specifically designed for comparing efficacy with a standard
antidepressant). Moreover, there continues to be lack of understanding
as to the precise roles that 5-HT and NE may play in depressive
disorders and in response to treatment. Studies seem to indicate that
both 5-HT and NE systems play pivotal roles in antidepressant response
through neuronal interplay and reciprocal interactions on cell bodies
of these two monoamines.5

Findings of Comparative Antidepressant Trials

For a comprehensive review of basic science and
clinical data relating to dual-mechanism antidepressants, the reader
is directed to an article by Schatzberg6 summarizing
existing data from comparative clinical trials. The largest number of
comparative trials are studies involving SSRIs and TCAs. A pattern of
better tolerability of SSRIs compared to TCAs is clearly evident in
these trials, as would be expected because the latter interact with
multiple receptors, including muscarinic, histaminic, and a-adrenergic
receptors, producing many unwanted side effects. These comparative
trials all suffer from the significant study design limitation that
they were not prospectively designed to specifically assess relative
efficacy of an SSRI with a TCA. Many of the comparative trials also
were not placebo-controlled. Because the studies were not powered
statistically to differentiate efficacy of an SSRI and TCA, for most
studies the degree of improvement was found not to differ significantly
for the comparative antidepressants.

Attempts to overcome these shortcomings in the data
have involved various statistical approaches, including the method of
meta-analysis (limitations of this statistical methodology were
discussed in a previous tutorial). Some meta-analyses of comparative
studies were confined to only placebo-controlled trials, others to
severely depressed subjects, inpatients, etc. These various
meta-analyses have found only trivial differences in efficacy between
SSRIs and TCAs.7 There are even fewer trials that allow
comparison of the more recent SSRI/NRI drugs (eg, venlafaxine or
duloxetine) with an SSRI.

A meta-analysis of venlafaxine studies involved eight clinical trials; only four of these were placebo-controlled.7
Three different comparative SSRIs were studied in these trials. It
appears that suboptimal dosage of the SSRI comparator was employed in
some of the studies. Although a higher remission rate was claimed for
venlafaxine, the data do not conclusively show the overall therapeutic
advantage of venlafaxine. Subsequent re-analyses, adjusted for some
of the shortcomings of the initial meta-analysis, also fail to
demonstate the clear-cut therapeutic advantage of venlafaxine over
SSRIs.7

In the case of the dual-mechanism drug duloxetine,
there have been even fewer published placebo-controlled comparative
studies with an SSRI. Similar to the findings with venlafaxine, the
data from comparative trials fail to show the statistical superiority
of the efficacy of duloxetine compared with that of an SSRI.8

Conclusion

Despite extensive research efforts over a span of
several decades, the precise mechanism of action of antidepressants
remains unclear. While both 5-HT and NE are deemed important mediators
of antidepressant drug response, uncertainty remains as to which
neurotransmitter may be the more critical in the pathophysiology of
mood disorders and for treatment of depression. Based on the fact that
current evidence from clinical trials is insufficient to allow valid
conclusions about relative efficacy, caution should be exercized in
accepting claims that multiple mechanism (two or more) drugs are
superior in efficacy to single mechanism antidepressants. More data
from prospective well-controlled comparative trials are warranted. PP

References

1. Owens MJ. Selectivity of antidepressants: from the monoamine hypothesis of depression to the SSRI revolution and beyond. J Clin Psychiatry. 2004;65(suppl 4):5-10.